Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing's sarcoma A673-xenograft growth and normalize tumor vascular architecture.

Abstract

Increasing experimental evidence suggests that IGF-1 may modulate tumor angiogenesis via activation of the expression of VEGF in Ewing sarcomas and rhabdomyosarcomas. This study investigates the effects of the PEGylated Adnectins™ CT-322, a VEGFR2-inhibitor and AT580Peg40, an IGF-1R inhibitor, as monotherapy and in combination in a murine A673 xenograft tumor model. The combination of Adnectins CT-322 and AT580Peg40 revealed a 83% reduction in tumor growth, a nearly 5 times lower vessel density, less necrotic areas and less appearance of intussusceptive angiogenesis. Monotherapy with IGF-1R or CT-322 revealed equally a significant inhibition of tumor and vessel growth. Combinatory inhibition of IGF-1R and VEGFR2 shows a downregulation of IGF-binding protein 2 and a compensatory upregulation of VEGF levels. Immunohistological analysis showed remodeling vascular effects of CT-322-treatment or combination therapy. The vascular architecture in Adnectin-treated tumors was characterized by a strong normalization of vasculature. 3D-evaluation in microvascular corrosion casts showed significantly higher intervascular and interbranching distances in Adnectin-treated tumors. CT-322-treatment and combinatory inhibition reveal a significant reduction of intussusceptive angiogenesis. These pronounced effects on tumor vasculature suggest potential therapeutic benefit of combinatorial IGF1- and VEGF-pathways inhibition in Ewing's sarcoma.

• Authors: Maximilian Ackermann, Brent A Morse, Vera Delventhal, Irvith M Carvajal, Moritz A Konerding
• Journal: Angiogenesis (Angiogenesis) Vol. 15 Issue 4 Pg. 685-95 (Dec 2012) ISSN: 1573-7209 [Electronic] Germany
• PMID: 22914877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, IGF Type 1
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• Cell Line, Tumor
• Down-Regulation
• Enzyme-Linked Immunosorbent Assay
• Female
• Humans
• Mice
• Mice, Nude
• Receptor, IGF Type 1 (metabolism)
• Sarcoma, Ewing (blood supply, pathology)
• Transplantation, Heterologous
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)